1. Field of the Invention
The present invention relates to a process for preparing an angiotension converting enzyme (ACE) inhibitor, and in particular to a process for preparing angiotension converting enzyme inhibitors such as intermediates of captopril, enalapril, quinapril and the like without using phosgene, diphosgene and triphosgene.
2. Description of the Related Arts
The synthesis of enalapril, an angiotensin coverting enzyme inhibitor which is used among other things in the treatment of blood pressure, by coupling amino acids has been disclosed in many patents. For example, in European Patent No. 0215335, enalaprils are prepared by reacting N-(s-ethoxycarbonyl-3-phenyl-propyl!-L-alanine with phosgene to form N-carboxylanhydride, followed by condensation with L-proline. This process uses noxious phosgene.
U.S. Pat. No. 5,359,086 discloses a process for the preparation of enalapril. According to the process, alkyl-L-alanine is reacted with a coupling agent, N,N-carbonyldiimidazole to form alkyl-L-alanine-N-carboxy anhydride. The alkyl-L-alanine-N-carboxy anhydride is then coupled with L-proline silyl ester hydrochloride to form the enalapril. The coupling agent, N,N-carbonyldiimidazole, is expensive.
In Spain Patent No. 544781, a process for preparing enalapril has been proposed. The process involves reacting alkyl-L-alanine with N-hydroxysuccinimide and dicyclohexylcarbodiimide (DCC) to form N'-succinimidyl ester and coupling the N'-succinimidyl ester with L-proline. However, it is hard to remove DCC.
U.S. Pat. No. 4,808,741 discloses a process for preparing pharmaceutically active carboxylalkyl dipeptides such as enalapril, lisinopril and the like. In the process, the amino acid group of a L-proline is protected with a benzyl protecting group. Subsequently, the protecting group is removed.